Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines - PubMed (original) (raw)

Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines

C M Wischik et al. Proc Natl Acad Sci U S A. 1996.

Abstract

In Alzheimer disease (AD) the microtubule-associated protein tau is redistributed exponentially into paired helical filaments (PHFs) forming neurofibrillary tangles, which correlate with pyramidal cell destruction and dementia. Amorphous neuronal deposits and PHFs in AD are characterized by aggregation through the repeat domain and C-terminal truncation at Glu-391 by endogenous proteases. We show that a similar proteolytically stable complex can be generated in vitro following the self-aggregation of tau protein through a high-affinity binding site in the repeat domain. Once started, tau capture can be propagated by seeding the further accumulation of truncated tau in the presence of proteases. We have identified a nonneuroleptic phenothiazine previously used in man (methylene blue, MB), which reverses the proteolytic stability of protease-resistant PHFs by blocking the tau-tau binding interaction through the repeat domain. Although MB is inhibitory at a higher concentration than may be achieved clinically, the tau-tau binding assay was used to identify desmethyl derivatives of MB that have Ki values in the nanomolar range. Neuroleptic phenothiazines are inactive. Tau aggregation inhibitors do not affect the tau-tubulin interaction, which also occurs through the repeat domain. Our findings demonstrate that biologically selective pharmaceutical agents could be developed to facilitate the proteolytic degradation of tau aggregates and prevent the further propagation of tau capture in AD.

PubMed Disclaimer

Similar articles

Cited by

References

    1. J Pharm Sci. 1972 Jul;61(7):1086-90 - PubMed
    1. Acta Neuropathol. 1996;91(6):633-41 - PubMed
    1. J Cell Biol. 1985 Jun;100(6):1905-12 - PubMed
    1. EMBO J. 1985 Dec 30;4(13B):3661-5 - PubMed
    1. Biol Psychiatry. 1986 Aug;21(10):915-20 - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources